Efavirenz is a well known non-nucleoside reverse transcriptase inhibitor (NNRTI) and is used in the highly active antiretroviral therapy (HAART) for the treatment of a human immunodeficiency virus (HIV) type 1 and is on the market for this use since 1998.
Efavirenz is chemically described as (S)-6-chloro-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one and has formula (I):

Several processes are known in the prior art to produce this active substance starting from the intermediate of formula (II):

This intermediate, (2S)-2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-ol, as a free base, is reacted with a chloroformate derivative under basic conditions to give, after from 1 to 6 hours of reaction, an alkyl carbamate intermediate (reaction of the amine moiety of intermediate (II) with the chloroformate derivative) that is then cyclized to yield Efavirenz.
Although this kind of reactions allows to obtain Efavirenz with an acceptable impurities profile, it has some disadvantages due to the length of the reaction time and/or the quite complicate work-up, as the alkyl carbamate intermediate must be isolated or the reaction mixture must be at least separated and concentrated before undergoing the cyclization step.
The one-pot synthesis starting from the compound of formula (II) as free base has been thus developed submitting such compound to a phosgenation reaction in an appropriate organic solvent or solvent mixtures.
In particular, the compound of formula (II) has been cyclized thus providing Efavirenz by means of phosgene in THF (see Journal of Organic Chemistry 1998, vol.63 pag. 8536-8543 (1998)) or using trichloromethylchloroformate (Diphosgene) in mixtures of THF and heptanes (see the patent publication WO2010/085978).
The main drawbacks of these processes is that the tetrahydrofuran solvent can react with the hydrochloric acid developed by the phosgenation reaction thus providing the by-product 4-choro-1-butanol and related addition products with the compound of formula (II), which are classified as a mutagenic substances.
It is therefore very important to avoid completely the formation of the impurity 4-chloro-1-butanol and related impurities which could be formed at ppm level either working at acid or a neutral or basic/buffered pH, in this last two cases due to the acid microenvironment generated by the release of hydrochloric acid during the phosgenation reaction.
The patent EP2384324B1 already discloses a method for removing also traces of the impurity 4-chloro-1-butanol, nevertheless it would be better to solve this problem in another way, i.e. avoiding the formation of these impurities, instead than to remove them.
The publication WO2010/032259 in example 2 discloses a process for the preparation of Efavirenz from the compound of formula (II) in 1 volume of acetone and 2 volumes of aq. sodium bicarbonate, adding triphosgene dissolved in 2 volumes of acetone. Differently from the prior art methods, Efavirenz was isolated by addition of water that promoted the precipitation of Efavirenz and then by filtration of the suspension. The declared purity of Efavirenz is 99.84%, nevertheless, repeating this experiment exactly in the same conditions (see example 6) and analyzing the product according to the analytical method used to analyze all the Efavirenz samples of the present invention as described in example 7 of the present application, the Efavirenz so prepared shows HPLC purity 99.21% a/a and HPLC assay 96.62% wt/wt, only.
In example 5 of WO2010/032259 the phosgenation reaction is carried out in propionitrile achieving a level of purity of 99.66%, lower than that achieved by the Efavirenz of example 1, according to that applicant.
The methods disclosed the examples 2 and 5 of WO2010/032259 have the drawback that the Efavirenz thus prepared have a relatively low chemical purity, i.e. lower than 99.80% HPLC a/a% and lower than 98.0% of HPLC assay wt/wt.
The publication WO2010/085978 discloses a method for the preparation of Efavirenz wherein the compound of formula (II) in a mixture of 2.6 volumes of THF, 2.6 volumes of heptanes and 7 volumes of aq. sodium bicarbonate is converted to Efavirenz with diphosgene. Efavirenz was obtained in 93% molar yield and shows HPLC purity higher than 99.8%. The main drawback of this method is that to isolate Efavirenz is necessary to distill many times the organic phase composed by Efavirenz dissolved in heptanes and THF, to remove the THF (until the THF content was less than 0.1% (GC)) so that Efavirenz polymorphic form 1 can be produced.
Other drawbacks of said method are:                the potential presence of traces of impurity 4-chloro-1-butanol and related impurity with the compound (II), due to the presence of THF;        the relatively high volumes of solvents used to perform the reaction, with negative impact on the productivity of the process.        
The application WO2012/048886 discloses a method for the preparation of Efavirenz from the compound of formula (II) solving the above problem related to the impurity 4-chloro-1-butanol by using mixtures of esters solvent, e.g. acetates, with heptanes, thus substituting the THF. Moreover, these particular solvent mixtures provides Efavirenz with high yields and improved purity over many of the previous known methods (but at the same levels of the process disclosed in WO2010/085978). Finally, the phosgenation reaction is carried out in relatively low volumes of solvents with a positive impact on the productivity of the process.
The main drawback of this last improved process is that, as other previous method for the preparation of Efavirenz by phosgention of the compound (II), such as that disclosed in WO2010/085978, after the end of the reaction and during the work up, it is necessary to perform the distillations of the organic solvents to isolate the product (see examples 6-11 wherein distillations where carried out to achieve a content of ethyl acetate comprised between 3 and 7 w/w%).
In particulars, in the methods disclosed in both the publications WO2010/085978 and WO2012/048886, after a first distillation of the organic phase, further additions of fresh heptanes followed by distillations were carried out to remove the other co-solvent being respectively THF or acetates.
On industrial scale, the distillation of organic phases requires a very long time, additional huge amounts of fresh heptanes and represents an actual bottom-neck for the large industrial production of Efavirenz. Furthermore, it impacts directly both on the productivity of the process and on the full cost of the product.